BBSRC EASTBIO DTP: Spinal cord repair by endogenous progenitor cells

Background
Zebrafish, in contrast to mammals, can repair a spinal cord injury and regain function. During regeneration, endogenous progenitor cells forming the ependyma in the spinal cord are activated and generate new neurons, some of which integrate into the spinal circuitry as new motor and interneurons. Similar cells exist in the ependymal zone of the spinal cord of mammals, including mice and humans. These have retained some progenitor function, but rarely generate neurons. Interestingly, when taken into culture, or transplanted into a neurogenic region, these adult mammalian ependymal cells can generate neurons. This points to a pivotal role of environmental signals shaping the regenerative response of spinal progenitor cells (reviewed in Becker et al., 2018).

Hypothesis
We hypothesise that spinal cord progenitors in the zebrafish express receptors for signals derived from the environment that control regenerative neurogenesis

Aims
In this project, the student will mine large datasets derived from single cell RNA sequencing from zebrafish (Becker lab) and mouse (Storey lab) adult spinal progenitor cells to find receptors that could transduce pro- and anti-neurogenic extracellular signals. The functional contribution of these receptors and associated pathways will then be tested in our fast zebrafish spinal cord regeneration paradigm (Ohnmacht et al., 2016; Tsarouchas et al., 2018). Receptors thought to be pro-regenerative (over-represented in zebrafish expression profiles) will be perturbed by our established rapid knock down approach using CRISPR/cas9 and by conditional over-expression of dominant-negative receptors using the TetOn system. The function of receptors that are over-represented in mouse expression profiles, and could therefore be anti-regenerative, will be assessed by overexpression in zebrafish progenitor cells. Read-outs will be progenitor cell proliferation, expression of differentiation factors, and numbers of newly generated neurons after spinal cord injury.

With this line of research, we hope to elucidate the signals that act on adult spinal cord progenitors cells and are necessary for successful neurogenesis during spinal cord regeneration. This project will provide targets for manipulations in endogenous mammalian progenitor cells, which invariably fail to generate neurons after injury.

Training outcomes
The student will be trained in complex cloning techniques, in vivo perturbations and analyses using the zebrafish system, confocal imaging techniques and bioinformatics approaches applied to systems biology.

Management
The student will be based in the Becker group in Edinburgh’s Centre for Discovery Brain Sciences (formally CNR). Bioinformatics analyses will be done in conjunction with the Storey group in Dundee. The student will visit Prof Storey’s lab in Dundee regularly particularly in the initial analysis phase (~6 months) and joint progress meetings will be held in Edinburgh or Dundee at 12-week intervals and there will be regular progress meetings via Skype (as needed).

Applications:
Completed application form along with your curriculum vitae should be sent to our PGR student team at [Email Address Removed]

References:
Please send the reference request form to two referees. Completed forms for University of Edinburgh College of Medicine and Veterinary Medicine project should be returned to [Email Address Removed] by the closing date: 5th December 2018.

It is your responsibility to ensure that references are provided by the specified deadline.

Download application and reference forms via:
https://www.ed.ac.uk/roslin/postgraduate/bbsrc-eastbio-dtp